ABSTRACT
Since the initial discovery of the oncogenic activity of WNT ligands our understanding of the complex roles for WNT signaling pathways in lung cancers has increased substantially. In the current review, the various effects of activation and inhibition of the WNT signaling pathways are summarized in the context of lung carcinogenesis. Recent evidence regarding WNT ligand transport mechanisms, the role of WNT signaling in lung cancer angiogenesis and drug transporter regulation and the importance of microRNA and posttranscriptional regulation of WNT signaling are also reviewed.
Subject(s)
Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Wnt Proteins/biosynthesis , Wnt Proteins/genetics , Wnt Signaling Pathway/physiology , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Genome-Wide Association Study/methods , Humans , Lung Neoplasms/drug therapy , MicroRNAs/biosynthesis , MicroRNAs/genetics , Wnt Signaling Pathway/drug effectsABSTRACT
Primycin-sulphate is a highly effective compound against Gram (G) positive bacteria. It has a potentially synergistic effect with vancomycin and statins which makes primycin-sulphate a potentially very effective preparation. Primycin-sulphate is currently used exclusively in topical preparations. In vitro animal hepatocyte and neuromuscular junction studies (in mice, rats, snakes, frogs) as well as in in vitro human red blood cell experiments were used to test toxicity. During these studies, the use of primycin-sulphate resulted in reduced cellular membrane integrity and modified ion channel activity. Additionally, parenteral administration of primycin-sulphate to mice, dogs, cats, rabbits and guinea pigs indicated high level of acute toxicity. The objective of this study was to reveal the cytotoxic and gene expression modifying effects of primycin-sulphate in a human system using an in vitro, three dimensional (3D) human hepatic model system. Within the 3D model, primycin-sulphate presented no acute cytotoxicity at concentrations 1µg/ml and below. However, even at low concentrations, primycin-sulphate affected gene expressions by up-regulating inflammatory cytokines (e.g., IL6), chemokines (e.g., CXCL5) and by down-regulating molecules of the lipid metabolism (e.g., peroxisome proliferator receptor (PPAR) alpha, gamma, etc). Down-regulation of PPAR alpha cannot just disrupt lipid production but can also affect cytochrome P450 metabolic enzyme (CYP) 3A4 expression, highlighting the need for extensive drug-drug interaction (DDI) studies before human oral or parenteral preparations can be developed.
Subject(s)
Imaging, Three-Dimensional , Macrolides/toxicity , Sulfates/toxicity , Cell Survival/drug effects , Chemokine CXCL5/genetics , Chemokine CXCL5/metabolism , Coculture Techniques , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A/metabolism , Dose-Response Relationship, Drug , Down-Regulation , Endpoint Determination , Hep G2 Cells , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Interleukin-6/genetics , Interleukin-6/metabolism , Lipid Metabolism/drug effects , Microarray Analysis , Models, Molecular , PPAR alpha/genetics , PPAR alpha/metabolism , PPAR gamma/genetics , PPAR gamma/metabolism , Up-RegulationABSTRACT
Members of the Wnt family of secreted glyco-lipo-proteins affect intrathymic T-cell development and are abundantly secreted by thymic epithelial cells (TECs) that create the specific microenvironment for thymocytes to develop into mature T-cells. During ageing, Wnt expression declines allowing adipoid involution of the thymic epithelium leading to reduced naïve T-cell output. The protein kinase C (PKC) family of serine-threonine kinases is involved in numerous intracellular biochemical processes, including Wnt signal transduction. In the present study, PKCδ expression is shown to increase with age and to co-localise with Wnt receptors Frizzled (Fz)-4 and -6. It is also demonstrated that connective tissue growth factor (CTGF) is a Wnt-4 target gene and is potentially involved in a negative feed-back loop of Wnt signal regulation. Down-regulation of Wnt-4 expression and activation of multiple repressor pathways suppressing ß-catenin dependent signalling in TECs contribute to the initiation of thymic senescence.